# NM_001377265.1(MAPT):c.2136C>T (p.Ser712=)

https://sugi.bio/variant/mapt-p-ser712

## Summary

**MAPT p.Ser712= (c.2136C>T)** is classified **Likely benign** in MAPT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-11). Very rare (popmax 0.000339%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the MAPT gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MAPT](https://sugi.bio/atlas/gene/MAPT/) |
| Protein change (HGVS p.) | p.Ser712= |
| Coding change (HGVS c.) | c.2136C>T |
| MANE Select transcript | [NM_001377265](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377265) |
| Variant type | single nucleotide variant |
| Location | chr17:46014287-46014287 (GRCh38) |
| ClinVar | [VCV4525968](https://www.ncbi.nlm.nih.gov/clinvar/variation/4525968/) |

**All HGVS expressions:** `LRG_660:g.124825C>T`, `LRG_660t1:c.1911C>T`, `LRG_660t2:c.2136C>T`, `NC_000017.10:g.44091653C>T`, `NC_000017.11:g.46014287C>T`, `NG_007398.2:g.124825C>T`, `NM_001123066.4:c.1965C>T`, `NM_001123067.4:c.873C>T`, `NM_001203251.2:c.780C>T`, `NM_001203252.2:c.867C>T`, `NM_001377265.1:c.2136C>T`, `NM_001377266.1:c.1845C>T`, `NM_001377267.1:c.771+9C>T`, `NM_001377268.1:c.693C>T`, `NM_005910.6:c.960C>T`, `NM_016834.5:c.786C>T`, `NM_016835.5:c.1911C>T`, `NM_016841.5:c.693C>T`, `NR_165166.1:n.791C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.37) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 4.017, GERP 7.21, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.88**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.19**, donor loss **0.37**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.37**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,179,936 in the highest group · 4/1,614,046 alleles overall — very rare (popmax 0.000339%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**MAPT** population constraint: LOEUF 0.723, pLI 2.1814e-05, missense-Z 2.4904; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **712** lies in a β-strand; a functional site (not glycated).

AlphaFold model confidence (whole protein): pLDDT 49.56, 0% of residues very-high.

**299 experimental structure(s)** (PDB): [10IJ](https://www.rcsb.org/structure/10IJ), [10IK](https://www.rcsb.org/structure/10IK), [1I8H](https://www.rcsb.org/structure/1I8H), [22JY](https://www.rcsb.org/structure/22JY), [28LJ](https://www.rcsb.org/structure/28LJ), [28LO](https://www.rcsb.org/structure/28LO) — incl. mutant structure 6GK7.

## What this gene does {#gene-function}

*Describes the biological roles of MAPT (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** MAPT's established molecular role includes enzyme inhibitor activity.


### Pathways affected {#pathways}

MAPT participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Caspase-mediated cleavage of cytoskeletal proteins](https://reactome.org/content/detail/R-HSA-264870) | curated |
| [Activation of AMPK downstream of NMDARs](https://reactome.org/content/detail/R-HSA-9619483) | other |
| [PKR-mediated signaling](https://reactome.org/content/detail/R-HSA-9833482) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** enzyme inhibitor activity, microtubule binding, SH3 domain binding, enzyme binding, protein kinase binding, apolipoprotein binding.

**Biological process:** microtubule cytoskeleton organization, DNA damage response, synapse assembly, learning or memory, memory, regulation of autophagy.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-11.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-11 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **712** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MAPT p.Ser712Phe](/variant/mapt-p-ser712phe). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MAPT variant pages (same residue, condition, or type): [MAPT p.Ser712Phe](/variant/mapt-p-ser712phe), [MAPT c.1999-10G>T](/variant/mapt-c-1999-minus-10g-t), [MAPT c.2091+16C>T](/variant/mapt-c-2091-plus-16c-t), [MAPT c.2091+3G>A](/variant/mapt-c-2091-plus-3g-a), [MAPT p.Arg798Trp](/variant/mapt-p-arg798trp), [MAPT p.Asn671Lys](/variant/mapt-p-asn671lys), [MAPT p.Asn688=](/variant/mapt-p-asn688), [MAPT p.Gln728His](/variant/mapt-p-gln728his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4525968). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*